Many new drugs are now available to be used by oncologists in treating patients with cancer. Often, tumors are more responsive to treatment when anti-cancer drugs are administered in combination to the patient than when the same drugs are administered individually and sequentially. One advantage of this approach is that the anti-cancer agents often act synergistically because the tumors cells are attacked simultaneously with agents having multiple modes of action. Thus, it is often possible to achieve more rapid reductions in tumor size by administering these drugs in combination. Another advantage of combination chemotherapy is that tumors are more likely to be eradicated completely and are less likely to develop resistance to the anti-cancer drugs being used to treat the patient.
One serious limitation of combination chemotherapy is that anti-cancer agents generally have severe side effects, even when administered individually. For example, the well known anti-cancer agent taxol causes neutroperia, neuropathy, mucositis, anemia, thrombocytopenia, bradycardia, diarrhea and nausea. Unfortunately, the toxicity of anti-cancer agents is generally additive when the drugs are administered in combination. As result, certain types of anti-cancer drugs are generally not combined. The combined toxic side-effects of those anti-cancer drugs that are administered simultaneously can place severe limitations on the quantities that can be used in combination. Often, it is not possible to use enough of the combination therapy to achieve the desired synergistic effects. Therefore, there is an urgent need for agents which can enhance the desirable tumor attacking properties of anti-cancer agents without further increasing their undesirable side-effects, and methods for synthesizing such agents.
It has been reported in the co-pending U.S. Provisional Applications entitled TAXOL ENHANCER COMPOUNDS, filed Jul. 10, 2001, (Application No. 60/304,252), TAXOL ENHANCER COMPOUNDS, filed Mar. 6, 2002 (Application No. 60/361,946) and TAXOL ENHANCER COMPOUNDS, filed Mar. 6, 2002 (Application No. 60/361,936) that certain bis[thio-hydrazide amide] compounds significantly enhance the anti-cancer activity of taxol and analogs of taxol. The entire teachings of these applications are incorporated herein by reference. Disclosed herein are methods of preparing these taxol enhancing compounds.
One embodiment of the present invention is a method of preparing a thiohydrazide product compound from a hydrazide starting compound. The hydrazide starting compound is represented by Structural Formula (I): 
The thiohydrazide product compound is represented by Structural Formula (II): 
In Structural Formulas (I)-(II), R1 and R2 are independently an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or R1 and R2, taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring. When R2 is an aryl group or a substituted aryl group, then R5 is a hydrazine protecting group; and when R2 is an aliphatic or substituted aliphatic group, then R5 is xe2x80x94H or a hydrazine protecting group. R10 is xe2x80x94H or a substituted or unsubstituted alkyl group (preferably xe2x80x94H or an unsubstituted alkyl group, more preferably xe2x80x94H or methyl). The method comprises the step of reacting the starting compound with a thionylating reagent.
Another embodiment of the present invention is a method of preparing a product compound represented by Structural Formula (III): 
The method comprises the step of reacting Zxe2x80x94C(O)xe2x80x94Yxe2x80x94(CO)xe2x80x94Z or HOxe2x80x94C(O)xe2x80x94Yxe2x80x94(CO)xe2x80x94OH and a carboxylic acid activating agent with the thiohydrazide represented by Structural Formula (II), wherein R5 is xe2x80x94H.
R1, R2 and R10 Structural Formula (III) are as described for Structural Formulas (I)-(II).
Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group. Preferably, Y is a covalent bond, xe2x80x94C(R7R8)xe2x80x94, xe2x80x94CH2CH2-, trans-(CHxe2x95x90CH)xe2x80x94, cis-(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CC)xe2x80x94 or a 1,4-phenylene group. More preferably, Y is a covalent bond or xe2x80x94C(R7R8)xe2x80x94.
R7 and R8 are each independently xe2x80x94H, an aliphatic or substituted aliphatic group, or R7 is xe2x80x94H and R8 is a substituted or unsubstituted aryl group, or, R7 and R8 taken together, are a C2-C6 substituted or unsubstituted alkylene group.
Each Z is a leaving group.
Another embodiment of the present invention is a method of preparing a product compound represented by Structural Formula (III) from a hydrazide starting compound represented by Structural Formula (I). The hydrazide starting compound is thionylated to form a thiohydrazide represented by Structural Formula (II), as described above. If R5 is xe2x80x94H, then Zxe2x80x94C(O)xe2x80x94Yxe2x80x94(CO)xe2x80x94Z or HOxe2x80x94C(O)xe2x80x94Yxe2x80x94(CO)xe2x80x94OH and a carboxylic acid activating agent is reacted with the thiohydrazide represented by Structural Formula (II) to form the product compound represented by Structural Formula (III), as described above. If R5 is a hydrazine protecting group, the hydrazine protecting group is first removed before reacting with Zxe2x80x94C(O)xe2x80x94Yxe2x80x94(CO)xe2x80x94Z. Z and Y are as described above.